本文選題：苯中毒 + 造血毒性　； 參考：《東南大學(xué)》2016年博士論文

【摘要】：苯暴露可引起造血系統(tǒng)惡性腫瘤,苯造血毒性的分子機(jī)制迄今尚未完全闡明。研究苯暴露早期階段到苯造血毒性發(fā)生發(fā)展過程中的關(guān)鍵事件及相關(guān)分子機(jī)制可以為苯中毒的診斷干預(yù)及早期預(yù)防提供科學(xué)依據(jù)。系統(tǒng)生物學(xué)研究顯示,機(jī)體細(xì)胞在生理病理不同狀態(tài)及疾病發(fā)生發(fā)展不同階段都具有特異性的代謝特征。本研究擬通過建立苯中毒小鼠模型,獲得小鼠外周循環(huán)及造血細(xì)胞的代謝特征,結(jié)合毒理學(xué)實(shí)驗(yàn)和生物信息學(xué)結(jié)果分析特征性改變內(nèi)源性小分子物質(zhì)的相關(guān)代謝通路;進(jìn)一步研究苯造血毒性相關(guān)的特異性代謝通路變化及作用機(jī)制;在此基礎(chǔ)上探討乙酰左旋肉堿干預(yù)是否影響苯暴露所致造血毒性、線粒體功能障礙和氧化應(yīng)激;最后初步探討了苯暴露對癌基因MDS-Evi1表達(dá)的影響以及該基因在造血干細(xì)胞凋亡調(diào)控中的作用機(jī)制。第一章苯中毒小鼠模型的建立及造血抑制毒性研究使用C3H/He小鼠,苯暴露劑量為0、150及300 mg/kg·bw,皮下注射方式染毒,每天1次,連續(xù)5天,共染毒4周,構(gòu)建苯中毒小鼠模型,模型構(gòu)建后進(jìn)行小鼠外周血常規(guī)、骨組織病理學(xué)、骨髓涂片、造血干細(xì)胞比例及造血集落形成能力檢查。結(jié)果顯示,通過皮下注射的染毒方式可成功構(gòu)建苯中毒小鼠模型,苯暴露對小鼠神經(jīng)系統(tǒng)初期為興奮效應(yīng),后期為抑制作用;苯暴露降低小鼠外周血白細(xì)胞、紅細(xì)胞、血紅蛋白和血小板計(jì)數(shù),引起貧血,組織病理學(xué)檢查結(jié)果顯示苯引起小鼠骨髓和脾臟造血抑制,骨髓涂片可見苯組小鼠骨髓細(xì)胞形態(tài)及增生異常、原始細(xì)胞比例明顯增加;此外,苯暴露還可引起小鼠LSK細(xì)胞比例下降,造血干祖細(xì)胞向GEMM和GM分化能力降低。以上結(jié)果表明苯暴露可引起小鼠外周血細(xì)胞計(jì)數(shù)降低、骨髓和脾臟造血抑制,骨髓細(xì)胞形態(tài)和增生分化異常;引起LSK細(xì)胞比例下降,GEMM和GM造血集落形成能力降低。第二章基于LC-MS研究苯暴露小鼠的代謝特征使用LC/MS技術(shù),研究苯暴露小鼠體循環(huán)(尿液、血漿)及靶器官(骨髓細(xì)胞)代謝特征,比較特異性內(nèi)源性小分子代謝產(chǎn)物及其涉及的代謝通路;結(jié)合血液毒性評價(jià)及代謝特征,篩選潛在的尿液和血漿中標(biāo)志血液系統(tǒng)早期損傷的代謝標(biāo)志物以及與苯造血毒作用相關(guān)的特異性代謝通路;此外,比較獲得在動(dòng)物模型骨髓細(xì)胞和血漿樣品中發(fā)現(xiàn)的共同差異代謝產(chǎn)物,在苯暴露人群血漿樣本中進(jìn)行驗(yàn)證。成功建立基于LC-MS的小鼠尿液、血漿和骨髓細(xì)胞代謝組學(xué)分析平臺(tái),結(jié)果顯示苯暴露擾亂尿液嘌呤、脂肪酸、色氨酸、谷�；奖彼岷蛠喚反x通路,干擾血漿色氨酸、組氨酸代謝、γ-谷氨酰循環(huán)、脂肪酸氧化以及脂肪酸代謝通路,導(dǎo)致骨髓細(xì)胞酪氨酸和苯丙氨酸代謝、賴氨酸分解、肉堿合成以及脂肪酸氧化代謝通路紊亂;比較苯暴露小鼠血漿和骨髓細(xì)胞中的差異性代謝通路,發(fā)現(xiàn)脂肪酸β氧化通路中的代謝分子均檢測到一致的改變,在收集的正常人群、苯暴露對照人群及苯暴露血象異常人群血漿樣本中進(jìn)行驗(yàn)證,發(fā)現(xiàn)苯暴露組人群血漿中左旋肉堿含量顯著下降,而乙酰左旋肉堿未發(fā)生明顯變化。以上結(jié)果提示苯暴露可干擾小鼠尿液、血漿和骨髓細(xì)胞中不同的代謝通路,其中,脂肪酸β氧化代謝通路是在外周樣本血漿及靶器官骨髓中的共同差異代謝通路,可能與苯造血毒性效應(yīng)密切相關(guān)。第三章苯暴露對脂肪酸氧化代謝通路的影響及機(jī)制研究將C3H/He小鼠暴露于0、20、40、80、160mg/kg·bw苯,以皮下注射方式染毒,每天1次,連續(xù)5天,共染毒4周,檢測苯暴露對小鼠骨髓細(xì)胞脂肪酸代謝通路關(guān)鍵酶mRNA水平和蛋白水平的影響,同時(shí)檢測對線粒體功能和氧化應(yīng)激的影響。結(jié)果顯示,苯暴露可影響脂肪酸氧化通路中肉堿穿梭酶和β氧化關(guān)鍵酶mRNA表達(dá),蛋白水平的驗(yàn)證表明苯暴露可增強(qiáng)小鼠骨髓細(xì)胞肉堿穿梭蛋白Cpt1a和Crat的表達(dá),使脂肪酸β氧化通路中Acaa2、A1dh112、Acadv1、Crot、Echs1和Hadha蛋白表達(dá)增加;苯暴露引起小鼠骨髓細(xì)胞中左旋肉堿、ATP和線粒體膜電位水平降低,同時(shí)還可引起H2O2、MDA和ROS等氧化損傷指標(biāo)水平增高。以上結(jié)果提示苯暴露可影響脂肪酸氧化通路中肉堿穿梭及β氧化過程,引起線粒體功能障礙和氧化應(yīng)激。第四章乙酰左旋肉堿干預(yù)對苯所致造血毒性的影響使用100 mg/kg·bw和200 mg/kg·bw左旋乙酰肉堿干預(yù)150 mg/kg·bw苯暴露小鼠,觀察乙酰左旋肉堿對苯所致造血毒性、線粒體功能障礙和氧化應(yīng)激的影響。結(jié)果顯示,左旋乙酰肉堿對苯暴露導(dǎo)致的小鼠外周血細(xì)胞減少無明顯作用,但是200 mg/kg·bw左旋乙酰肉堿干預(yù)可以明顯增加苯暴露組小鼠全骨髓細(xì)胞數(shù)量、LSK造血干細(xì)胞比例和Lini-C-kit-Sca-1+造血祖細(xì)胞比例;乙酰左旋肉堿干預(yù)可以在一定程度上減輕苯所致的線粒體損傷,可降低苯暴露所致H202、MDA和ROS增加;200 mg/kg乙酰左旋肉堿干預(yù)可明顯降低苯暴露小鼠骨髓細(xì)胞尾部DNA含量、尾距和尾長,減輕DNA損傷。以上結(jié)果提示乙酰左旋肉堿干預(yù)可在一定程度上減輕苯所致小鼠全骨髓細(xì)胞、LSK造血干細(xì)胞損傷,其作用機(jī)制可能涉及減少苯暴露所致氧化應(yīng)激,降低苯誘導(dǎo)DNA損傷。第五章MDS-Evi1基因與苯毒性關(guān)系初探及其參與骨髓造血干細(xì)胞凋亡調(diào)控的研究使用0、1μm、5μm和10μm1,4-苯醌染毒小鼠骨髓lin-細(xì)胞24小時(shí),檢測細(xì)胞增殖、細(xì)胞凋亡以及MECOM基因表達(dá),同時(shí)在苯暴露小鼠骨髓細(xì)胞中檢測MECOM蛋白的表達(dá);隨后建立在ME表達(dá)細(xì)胞中特異性敲除Bax和Bak基因的MEm2小鼠,觀察LSK細(xì)胞數(shù)量、細(xì)胞增殖、細(xì)胞凋亡、集落形成能力以及競爭性骨髓移植后LT-HSCs的重建能力。結(jié)果顯示,5μm和1Oμm1,4-苯醌組細(xì)胞存活率明顯下降,1μM 1,4-苯醌組細(xì)胞的凋亡率最大;隨著染毒劑量的增加,細(xì)胞MECOM基因表達(dá)增加;體內(nèi)實(shí)驗(yàn)結(jié)果顯示160 mg/kg·bw苯暴露引起MECOM蛋白表達(dá)顯著增加。ME基因敲除小鼠LSK細(xì)胞的數(shù)量下降,增殖加速,凋亡率增加,且這種凋亡是造血干細(xì)胞自發(fā)性的;在ME表達(dá)細(xì)胞中特異性地敲除Bax和Bak基因可使LSK細(xì)胞數(shù)量和增殖正常,骨髓細(xì)胞CFU-GEMM和CFU-GM集落形成能力增加,可以挽救MEm2/m2小鼠LT-HSCs重建能力。以上結(jié)果提示苯暴露可增加癌基因MDS-Evi1表達(dá)水平,該基因通過Bax和Bak通路參與造血干細(xì)胞增殖、凋亡和重建功能調(diào)控�？偨Y(jié)綜上,本研究成功建立苯中毒小鼠模型,結(jié)果表明苯暴露抑制造血,同時(shí)可擾亂小鼠尿液、血漿和骨髓細(xì)胞不同代謝通路,其中,脂肪酸β氧化代謝通路可能與苯造血毒性密切相關(guān);進(jìn)一步研究表明苯暴露引起脂肪酸氧化通路中肉堿穿梭及β氧化過程中關(guān)鍵酶表達(dá)增加、線粒體功能障礙和氧化應(yīng)激;而給予乙酰左旋肉堿干預(yù)可在一定程度上減輕苯所致小鼠造血系統(tǒng)損傷,其作用機(jī)制可能涉及減少苯暴露所致氧化應(yīng)激和DNA損傷;此外,苯暴露可增加癌基因MDS-Evi1表達(dá)水平,該基因通過Bax和Bak通路參與造血干細(xì)胞增殖、凋亡和重建功能調(diào)控。
[Abstract]:Benzene exposure can cause malignant tumor of hematopoietic system. The molecular mechanism of hematopoietic toxicity of benzene has not been fully elucidated so far. The key events and related molecular mechanisms in the study of the early stage of benzene exposure to the development of benzene hematopoiesis and related molecular mechanisms can provide scientific basis for the diagnosis and early prevention of benzene poisoning. Somatic cells have specific metabolic characteristics in different stages of physiological and pathological conditions and different stages of disease and development. This study aims to establish a mouse model of benzene poisoning to obtain the metabolic characteristics of peripheral circulation and hematopoietic cells in mice, and combine the toxicological experiments and bioinformatics results to analyze the characteristics of endogenous small molecular substances. Related metabolic pathways; further study on the specific metabolic pathways related to the hematopoietic toxicity of benzene and the mechanism of action; and on the basis of this, whether acetyl L-carnitine intervention affects hematopoiesis, mitochondrial dysfunction and oxidative stress induced by benzene exposure; finally, the effect of benzene exposure on the expression of oncogene MDS-Evi1 and the effect of benzene exposure on the expression of oncogene are discussed. The mechanism of gene in the regulation of hematopoietic stem cell apoptosis. In Chapter 1, the establishment of the mice model of benzene poisoning and the study of hematopoietic inhibition toxicity were used in C3H/He mice, the exposure dose of benzene was 0150 and 300 mg/kg BW, the subcutaneous injection was poisoned, 1 times a day for 5 days and a total of 4 weeks were infected, and the model of benzene poisoning mice was constructed and the model of mice was constructed outside the mice. Peripheral blood routine, bone histopathology, bone marrow smear, hematopoietic stem cell ratio and hematopoietic colony forming ability examination. The results showed that the mice model of benzene poisoning could be successfully constructed by subcutaneous injection. Benzene exposure was excited in the early stage of the nervous system and later was inhibited, and benzene exposure decreased peripheral blood leukocytes in mice. Erythrocyte, hemoglobin and platelet count, causing anemia. Histopathological examination results showed that benzene caused bone marrow and spleen hematopoiesis in mice. Bone marrow smears showed abnormal morphology and proliferation of bone marrow cells in benzene group, and the proportion of primitive cells increased significantly. In addition, benzene exposure could cause the decrease of LSK cells in mice and hematopoietic progenitor cells. The differentiation of GEMM and GM decreased. The above results showed that benzene exposure could reduce the number of peripheral blood cells in mice, bone marrow and spleen hematopoiesis, bone marrow cell morphology and proliferation and differentiation, the decrease of LSK cells and the decrease of GEMM and GM hematopoiesis. The second chapter was based on LC-MS to study the metabolic characteristics of mice exposed to benzene. LC/MS technology studies the metabolic characteristics of benzene exposed mice body circulation (urine, plasma) and target organs (bone marrow cells), compares the specific endogenous small molecular metabolites and their metabolic pathways, and combines the evaluation of blood toxicity and metabolic characteristics to screen the metabolic markers for the early damage of the blood system in the urine and blood plasma. Specific metabolic pathways related to the effect of benzene on hematopoiesis; in addition, the common differential metabolites found in the animal model bone marrow cells and plasma samples were compared in the plasma samples of the exposed population of benzene. A successful establishment of a LC-MS based mouse urine, plasma and bone marrow cell metabolic analysis platform was established. The results showed that benzene exposure was exposed. Disrupting urine purine, fatty acids, tryptophan, glutamyl phenylalanine and arginine metabolic pathways, interfering with plasma tryptophan, histidine metabolism, gamma glutamyl cycle, fatty acid oxidation and fatty acid metabolism pathway, leading to tyrosine and phenylalanine metabolism in bone marrow cells, lysine decomposition, carnitine synthesis, and fatty acid oxidation metabolic pathways turbulence The metabolic pathways in the plasma and bone marrow cells of mice exposed to benzene were compared, and the metabolic molecules in the fatty acid beta oxidation pathway were detected by the same changes. In the normal population, the benzene exposed control population and the blood samples from the abnormal group of benzene exposed hemogram were tested, and the plasma L-carnitine in the exposed group of benzene was found. The content of acetyl L-carnitine did not change significantly. The above results suggested that benzene exposure could interfere with the different metabolic pathways in the urine, plasma and bone marrow cells of mice, in which the fatty acid beta oxidation pathway is a common metabolic pathway in the peripheral blood samples and the target organ bone marrow, and may be closely related to the toxic effect of benzene on hematopoiesis. The influence and mechanism of benzene exposure on the oxidative metabolic pathway of fatty acids in third chapters, C3H/He mice were exposed to 0,20,40,80160mg/kg BW benzene, exposed to subcutaneous injection, 1 times a day for 5 days, for 4 weeks, and the effects of benzene exposure on the level of mRNA and protein level of the key enzymes of fatty acid metabolite pathway in mice bone marrow cells were detected. The results showed that benzene exposure could affect the expression of carnitine shuttle and beta oxidation key enzyme mRNA in the fatty acid oxidation pathway, and the protein level showed that benzene exposure could enhance the expression of carnitine shuttle protein Cpt1a and Crat in mouse bone marrow cells and make Acaa2, A1dh1 in the fatty acid beta oxidation pathway. 12, Acadv1, Crot, Echs1 and Hadha protein expression increased; benzene exposure caused the decrease of L-carnitine, ATP and mitochondrial membrane potential in mouse bone marrow cells, and also increased the levels of H2O2, MDA, ROS and other oxidative damage indicators. The above results suggest that benzene exposure can affect the process of carnitine shuttle and beta oxidation in the fatty acid oxidation pathway, causing lines. The effect of acetyl L-carnitine intervention on hematopoiesis induced toxicity of benzene in fourth chapters: the effects of 100 mg/kg. BW and 200 mg/kg. BW L-acetylcarnitine on 150 mg/kg. BW benzene exposure mice. The effects of acetyl L-carnitine on hematopoiesis, mitochondrial dysfunction and oxidative stress were observed. Acetyl carnitine had no significant effect on the decrease of peripheral blood cells in mice caused by benzene exposure, but the intervention of 200 mg/kg. BW levoacetyl carnitine could significantly increase the number of all bone marrow cells in the mice exposed to benzene, the proportion of LSK hematopoietic stem cells and the proportion of Lini-C-kit-Sca-1+ hematopoietic progenitor cells, and the ethyl L-carnitine intervention could be reduced to a certain extent. The mitochondrial damage caused by light benzene could reduce the increase of H202, MDA and ROS caused by benzene exposure, and the intervention of 200 mg/kg acetyl L-carnitine could significantly reduce the DNA content, tail length and tail length of mice bone marrow cells exposed to benzene, and reduce DNA damage. The results suggested that acetyl L-carnitine intervention could reduce the total bone marrow cells of benzene induced mice to a certain extent, LSK hematopoietic stem cell injury, its mechanism may be involved in reducing oxidative stress caused by benzene exposure and reducing benzene induced DNA damage. Fifth the relationship between MDS-Evi1 gene and benzene toxicity and its involvement in the regulation of bone marrow hematopoietic stem cell apoptosis using 0,1 mu m, 5 m and 10 micron benzquinone in mice bone marrow lin- cells for 24 hours, and detection of cell proliferation. Colonization, apoptosis and expression of MECOM gene, and the expression of MECOM protein in bone marrow cells exposed to benzene, and subsequently established in MEm2 mice that specifically knock out Bax and Bak genes in ME expression cells, observe the number of LSK cells, cell proliferation, cell apoptosis, colony forming ability and LT-HSCs reconstruction after competitive bone marrow transplantation. The results showed that the cell survival rate of 5 m and 1O m1,4- quinone group decreased significantly, the apoptosis rate of the 1 M 1,4- benzone group was the largest, and the expression of MECOM gene in the cells increased with the increase of dose. The experimental results showed that the expression of MECOM protein in the 160 mg/kg / BW benzene exposure significantly increased the number of LSK cells in the.ME gene knockout mice. The proliferation accelerated and the apoptosis rate increased, and the apoptosis was spontaneous. The specific knockout of the Bax and Bak genes in the ME expression cells could make the number and proliferation of LSK cells normal, the CFU-GEMM and CFU-GM colony formation ability of the bone marrow cells increased, which could save the LT-HSCs reconstruction ability of MEm2/m2 mice. The above results suggest that the benzene exposure can be increased. The expression level of oncogene MDS-Evi1, which participates in the proliferation, apoptosis and reconstruction function of hematopoietic stem cells through Bax and Bak pathway, has been successfully established in this study. The results show that benzene exposure inhibits hematopoiesis and can disturb the different metabolic pathways of urine, plasma and bone marrow cells in mice, including fatty acid beta oxygen. The metabolic pathway may be closely related to the hematopoiesis of benzene. Further studies have shown that the expression of key enzymes in the process of carnitine shuttle and beta oxidation in the fatty acid oxidation pathway is increased, and the mitochondrial dysfunction and oxidative stress are increased in the fatty acid oxidation pathway, while acetyl L-carnitine intervention can reduce the hematopoietic system damage caused by benzene in mice to a certain extent. Its mechanism may be involved in reducing oxidative stress and DNA damage caused by benzene exposure. In addition, benzene exposure can increase the expression of oncogene MDS-Evi1, which is involved in the regulation of hematopoietic stem cell proliferation, apoptosis and reconstruction through the Bax and Bak pathways.
【學(xué)位授予單位】：東南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R135.12

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